Trialkyl-lock-facilitated polymeric prodrugs of amino-containing bioactive agents
First Claim
Patent Images
1. A compound comprising the formula:
- ##STR14## wherein;
B is H, OH, OSiR13 or a residue of an amine-containing target moiety;
G is ##STR15## or CH2 ;
Y1-2 are independently O or S;
M is X or Q;
X is an electron withdrawing group;
Q is a moiety containing a free electron pair positioned three to six atoms from C(═
Y2);
R1, R4, R7, R8, R9, R10 and R13 are independently selected from the group consisting of hydrogen, C1-6 alkyls, C3-12 branched alkyls, C3-8 cycloalkyls, C1-6 substituted alkyls, C3-8 substituted cycloalkyls, aryls, substituted aryls, aralkyls, C1-6 heteroalkyls and substituted C1-6 heteroalkyls;
R2, R3, R5 and R6 are independently selected from the group consisting of hydrogen, C1-6 alkyls, C1-6 alkoxy, phenoxy, C1-8 heteroalkyls, C1-8 heteroalkoxy, substituted C1-6 alkyls, C3-8 cycloalkyls, C3-8 substituted cycloalkyls, aralkyls, aryls, substituted aryls, such as aryls substituted with halo-, nitro- and cyano-;
carboxy-, C1-6 carboxyalkyls and C1-6 alkyl carbonyls;
(m) is zero or one;
(n) is zero or a positive integer;
(p) is zero, one or two; and
R11 is a substantially non-antigenic polymer.
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Abstract
The present invention is directed to double prodrugs containing polymeric-based transport forms. These polymeric prodrugs are preferably of the formula: ##STR1## wherein: B is a leaving group or a residue of an amine-containing target moiety;
G is ##STR2## or CH2 ; Y1-2 are independently O or S;
M is X or Q; where X is an electron withdrawing group and Q is a moiety containing a free electron pair positioned three to six atoms from C(═Y2);
R1, R4, R7, R8, R9, R10 and R13 are independently selected from the group consisting of hydrogen, C1-6 alkyls, C3-12 branched alkyls, C3-8 cycloalkyls, C1-6 substituted alkyls, C3-8 substituted cycloalkyls, aryls, substituted aryls, aralkyls, C1-6 heteroalkyls, substituted C1-6 heteroalkyls;
R2, R3, R5 and R6 are independently selected from the group consisting of hydrogen, C1-6 alkyls, C1-6 alkoxy, phenoxy, C1-8 heteroalkyls, C1-8 heteroalkoxy, substituted C1-6 alkyls, C3-8 cycloalkyls, C3-8 substituted cycloalkyls, aralkyls, aryls, substituted aryls, such as aryls substituted with halo-, nitro- and cyano-; carboxy-, C1-6 carboxyalkyls and C1-6 alkyl carbonyls;
(m) is zero or one;
(n) is zero or a positive integer;
(p) is zero, one or two; and
R11 is a substantially non-antigenic polymer.
The first prodrug is generated when the polymeric portion of the double prodrug is cleaved and the parent molecule is generated rapidly thereafter in vivo, as a result of a trialkyl lock type lactonization-type reaction.
94 Citations
42 Claims
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1. A compound comprising the formula:
- ##STR14## wherein;
B is H, OH, OSiR13 or a residue of an amine-containing target moiety;G is ##STR15## or CH2 ;
Y1-2 are independently O or S;M is X or Q; X is an electron withdrawing group; Q is a moiety containing a free electron pair positioned three to six atoms from C(═
Y2);R1, R4, R7, R8, R9, R10 and R13 are independently selected from the group consisting of hydrogen, C1-6 alkyls, C3-12 branched alkyls, C3-8 cycloalkyls, C1-6 substituted alkyls, C3-8 substituted cycloalkyls, aryls, substituted aryls, aralkyls, C1-6 heteroalkyls and substituted C1-6 heteroalkyls; R2, R3, R5 and R6 are independently selected from the group consisting of hydrogen, C1-6 alkyls, C1-6 alkoxy, phenoxy, C1-8 heteroalkyls, C1-8 heteroalkoxy, substituted C1-6 alkyls, C3-8 cycloalkyls, C3-8 substituted cycloalkyls, aralkyls, aryls, substituted aryls, such as aryls substituted with halo-, nitro- and cyano-;
carboxy-, C1-6 carboxyalkyls and C1-6 alkyl carbonyls;(m) is zero or one; (n) is zero or a positive integer; (p) is zero, one or two; and R11 is a substantially non-antigenic polymer. - View Dependent Claims (2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 30, 31, 32, 33, 34, 35, 36)
- ##STR14## wherein;
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27. A method for preparing a trialkyl lock based prodrug transport form, comprising:
- a. providing an intermediate compound (III) ##STR18## where M2 is a cleavable or reversible protecting group
B is H, OH, OSiR13 or a residue of an amine-containing target moiety; G is ##STR19## or CH2 ;
Y1-2 are independently O or S;M is X or Q; X is an electron withdrawing group; Q is a moiety containing a free electron pair positioned three to six atoms from C(═
Y2);R1, R4, R7, R8, and R13 are independently selected from the group consisting of hydrogen, C1-6 alkyls, C3-12 branched alkyls, C3-8 cycloalkyls, C1-6 substituted alkyls, C3-8 substituted cycloalkyls, aryls, substituted aryls, aralkyls, C1-6 heteroalkyls and substituted C1-6 heteroalkyls; R2, R3, R5 and R6 are independently selected from the group consisting of hydrogen, C1-6 alkyls, C1-6 alkoxy, phenoxy, C1-8 heteroalkyls, C1-8 heteroalkoxy, substituted C1-6 alkyls, C3-8 cycloalkyls, C3-8 substituted cycloalkyls, aralkyls, aryls, substituted aryls, such as aryls substituted with halo-, nitro- and cyano-;
carboxy-, C1-6 carboxyalkyls and C1-6 alkyl carbonyls;(n) is zero or a positive integer; (p) is zero, one or two; and b. treating the intermediate compound (III) with an acid; and c. reacting the unprotected intermediate with a compound capable of reacting with an M and forming a compound of Formula (IV);
##STR20## where B2 is a leaving group;R9, and R10 are independently selected from the group consisting of hydrogen, C1-6 alkyls, C3-12 branched alkyls, C3-8 cycloalkyls, C1-6 substituted alkyls, C3-8 substituted cycloalkyls, aryls, substituted aryls, aralkyls, C1-6 heteroalkyls and substituted C1-6 heteroalkyls; R11 is a substantially non-antigenic polymer; and all other variables are as set forth above.
- a. providing an intermediate compound (III) ##STR18## where M2 is a cleavable or reversible protecting group
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28. A method for preparing a trialkyl lock based prodrug transport form, comprising:
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a. providing an intermediate compound (III) ##STR21## where M2 is a cleavable or reversible protecting group B is H, OH, OSiR13 or a residue of an amine-containing target moiety; G is ##STR22## or CH2 ;
Y1-2 are independently O or S;M is X or Q; X is an electron withdrawing group; Q is a moiety containing a free electron pair positioned three to six atoms from C(═
Y2);R1, R4, R7, R8, and R13 are independently selected from the group consisting of hydrogen, C1-6 alkyls, C3-12 branched alkyls, C3-8 cycloalkyls, C1-6 substituted alkyls, C3-8 substituted cycloalkyls, aryls, substituted aryls, aralkyls, C1-6 heteroalkyls and substituted C1-6 heteroalkyls; R2, R3, R5 and R6 are independently selected from the group consisting of hydrogen, C1-6 alkyls, C1-6 alkoxy, phenoxy, C1-8 heteroalkyls, C1-8 heteroalkoxy, substituted C1-6 alkyls, C3-8 cycloalkyls, C3-8 substituted cycloalkyls, aralkyls, aryls, substituted aryls, such as aryls substituted with halo-, nitro- and cyano-;
carboxy-, C1-6 carboxyalkyls and C1-6 alkyl carbonyls;(n) is zero or a positive integer; (p) is zero, one or two; and b. coupling the intermediate compound (III) to an amine-containing compound to form a trialkyl lock-based intermediate; c. deprotecting the trialkyl lock-based intermediate with an acid; and d. reacting the unprotected trialkyl lock-based intermediate intermediate with an activated polymer to form a compound of the formula(I);
##STR23## R9, R10, are independently selected from the group consisting of hydrogen, C1-6 alkyls, C3-12 branched alkyls, C3-8 cycloalkyls, C1-6 substituted alkyls, C3-8 substituted cycloalkyls, aryls, substituted aryls, aralkyls, C1-6 heteroalkyls and substituted C1-6 heteroalkyls;R11 is a substantially non-antigenic polymer; and all other variables are as set forth above. - View Dependent Claims (29, 37, 38, 39, 40, 41, 42)
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Specification
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Current AssigneeEnzon Pharmaceuticals Inc. (Icahn Associates Holding LLC)
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Original AssigneeEnzon Pharmaceuticals Inc. (Icahn Associates Holding LLC)
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InventorsGreenwald, Richard B., Choe, Yun H.
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Primary Examiner(s)Richter, Johann
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Assistant Examiner(s)Delaney, Patrick R.
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Application NumberUS09/000,676Time in Patent Office651 DaysField of Search424/85.1, 424/85.2, 424/85.4, 424/78.37, 530/351, 530/402, 548/572, 558/230, 558/273, 560/160, 560/170, 560/186US Class Current424/78.37CPC Class CodesA61K 47/60 the organic macromolecular ...A61P 31/04 Antibacterial agentsA61P 35/00 Antineoplastic agentsA61P 43/00 Drugs for specific purposes...C07B 2200/11 Compounds covalently bound ...C07C 237/22 having nitrogen atoms of am...C07C 271/16 to carbon atoms of hydrocar...C07C 271/22 to carbon atoms of hydrocar...
